Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, highly lethal disease marked by extreme resistance to conventional therapies. Thus, there is a need to better understand the signaling pathways that drive PDAC, and to identify new potential targets for molecularly-targeted therapies to treat this disease. The K-ras proto-oncogene is mutated in the vast majority of PDAC and is necessary for the maintenance of the transformed phenotype of many PDAC cell lines. Oncogenic K-ras also plays a critical role in the initiation and progression of PDAC. Expression of oncogenic K-ras in mouse pancreatic epithelium induces ductal metaplasia, followed by formation of preneoplastic lesions, mouse pancreatic intraepithelial neoplasias (mPanINs) with the ability to progress to PDAC. These observations strongly suggest that oncogenic K-ras drives a multi-step process of pancreatic carcinogenesis. However, efforts to therapeutically target oncogenic K-ras have not been successful, leading to intensive efforts to identify critical downstream effectors of K-ras that are more amenable to therapeutic intervention. We have found that protein kinase C iota (PKC?), a known downstream effector of oncogenic K-ras in other systems, is highly over-expressed in human pancreatic tumors, and that high tumor PKC??expression correlates with poor patient survival. Furthermore, we have found that PKC? is required for the transformed growth and tumorigenicity of PDAC cells expressing oncogenic K-ras. PKC? drives transformed growth of PDAC cells, at least in part, through activation of an oncogenic PKC?-Rac1- MEK/ERK1/2 signaling axis. Based on these observations, and our preliminary data, we hypothesize that PKC? is required for oncogenic K-ras-mediated PDAC initiation and progression. We further hypothesize that the PKC?/Rac1-MEK/ERK1/2 signaling axis drives pancreatic carcinogenesis by regulating specific pro-carcinogenic signaling pathways. Three interrelated specific aims are designed to test these hypotheses. 1) To dissect the PKC?-regulated signaling mechanisms required for K-ras-mediated metaplasia. 2) To assess the role of PKC? in K-rasG12D-mediated initiation of pancreatic carcinogenesis and mPanIN formation in vivo. 3) To determine the role of PKC? in K-rasG12D-mediated PDAC. Due to the poor prognosis of PDAC patients, the NCI has identified pancreatic cancer research as a funding priority. The proposed studies are highly translational and 100% relevant to pancreatic cancer, with the goal of characterizing the requirement for PKC? in oncogenic K-ras-mediated pancreatic metaplasia, mPanIN formation and progression to PDAC. In addition, we will characterize the molecular mechanism(s) by which PKC? contributes to the carcinogenic process. The significance of these studies is enhanced by the fact that the ability to therapeutically target PKC? currently exists. Thus, insights gained through these pre-clinical studies may be translated into new treatment strategies for PDAC patients. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is a highly lethal disease, marked by extreme resistance to conventional therapies; thus, there is a need to identify new potential targets for molecularly-targeted therapies to treat this disease. This project will test the hypothesis that protein kinase C iota (PKC?) is required for initiation and progression of pancreatic cancer using a well-characterized mouse model of this disease. An FDA-approved molecularly- targeted inhibitor of aPKC signaling is available as a cancer chemotherapeutic; therefore, the proposed studies have the potential to have immediate impact on the clinical practice of treatment of pancreatic cancer patients.